Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.


Impact of germline mutations in cancer-predisposing genes on long-term survival in patients with epithelial ovarian cancer



Several clinical and tumour factors impact on ovarian cancer survival. It is important to evaluate if germline mutations impact long-term outcomes among patients with epithelial ovarian cancer.


We followed 1422 Ontario women with ovarian cancer. Clinical information was obtained from medical records and vital status was determined by registry linkage. Germline genetic testing was performed for 12 susceptibility genes. We estimated 20-year cancer-specific survival according to various factors.


Twenty-year survival was inferior for women with serous cancers vs. other types (22.3% vs. 68.6%; P < 0.0001). Of the 1422 patients, 248 (17.4%) carried a germline mutation; 119 BRCA1; 75 BRCA2; 7 in a mismatch repair (MMR) gene and 47 in one of seven other genes. Among serous patients, 20-year survival was 28.9% for similar for women with a BRCA1 (28.9%), BRCA2 (21.2%) or no mutation (21.6%). Among endometrioid patients, 20-year survival was poor for women with a BRCA vs. no mutation (47.3% vs. 70.4%; P = 0.004). Six of the seven MMR mutation carriers are currently alive, while all three PALB2 mutation carriers died within 3 years of diagnosis. Among women with Stage III/IV serous cancers, 20-year survival was 9.4% for those with vs. 46.5% for those with no residual disease (HR = 2.91; 95% CI 2.12–4.09, P < 0.0001).


The most important predictor of long-term survival was no residual disease post surgery. BRCA mutation status was not predictive of long-term survival while those with MMR mutations had excellent survival. Larger studies on PALB2 carriers are needed.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type



Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Ovarian cancer-specific survival by histologic subtype.
Fig. 2: Ovarian cancer-specific survival by serous subtype only.

Data availability

Data underlying these analyses are not available in this manuscript, however, they are available through the authors or through dbGaP for the publicly available data.


  1. Sopik V, Iqbal J, Rosen B, Narod SA. Why have ovarian cancer mortality rates declined? Part II. Case-fatality. Gynecol Oncol. 2015;138:750–6.

    Article  Google Scholar 

  2. Hu C, Hart SN, Gnanaolivu R, Huang H, Lee KY, Na J, et al. A population-based study of genes previously implicated in breast cancer. N. Engl J Med. 2021;384:440–51.

    Article  Google Scholar 

  3. Tewari D, Java JJ, Salani R, Armstrong DK, Markman M, Herzog T, et al. Long-term survival advantage and prognostic factors associated with intraperitoneal chemotherapy treatment in advanced ovarian cancer: a gynecologic oncology group study. J Clin Oncol. 2015;33:1460–6.

    Article  CAS  Google Scholar 

  4. Bristow RE, Tomacruz RS, Armstrong DK, Trimble EL, Montz FJ. Survival effect of maximal cytoreductive surgery for advanced ovarian carcinoma during the platinum era: a meta-analysis. J Clin Oncol. 2002;20:1248–59.

    Article  Google Scholar 

  5. du Bois A, Reuss A, Pujade-Lauraine E, Harter P, Ray-Coquard I, Pfisterer J. Role of surgical outcome as prognostic factor in advanced epithelial ovarian cancer: a combined exploratory analysis of 3 prospectively randomized phase 3 multicenter trials: by the Arbeitsgemeinschaft Gynaekologische Onkologie Studiengruppe Ovarialkarzinom (AGO-OVAR) and the Groupe d’Investigateurs Nationaux Pour les Etudes des Cancers de l’Ovaire (GINECO). Cancer. 2009;115:1234–44.

    Article  Google Scholar 

  6. Chang SJ, Bristow RE. Evolution of surgical treatment paradigms for advanced-stage ovarian cancer: redefining ‘optimal’ residual disease. Gynecol Oncol. 2012;125:483–92.

    Article  Google Scholar 

  7. Konstantinopoulos PA, Norquist B, Lacchetti C, Armstrong D, Grisham RN, Goodfellow PJ, et al. Germline and somatic tumor testing in epithelial ovarian cancer: ASCO Guideline. J Clin Oncol. 2020;38:1222–45.

    Article  Google Scholar 

  8. McLaughlin JR, Rosen B, Moody J, Pal T, Fan I, Shaw PA, et al. Long-term ovarian cancer survival associated with mutation in BRCA1 or BRCA2. J Natl Cancer Inst. 2013;105:141–8.

    Article  CAS  Google Scholar 

  9. Tew WP, Lacchetti C, Ellis A, Maxian K, Banerjee S, Bookman M, et al. PARP inhibitors in the management of ovarian cancer: ASCO Guideline. J Clin Oncol. 2020;38:3468–93.

    Article  Google Scholar 

  10. Karczewski KJ, Francioli LC, Tiao G, Cummings BB, Alföldi J, Wang Q, et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature. 2020;581:434–43.

    Article  CAS  Google Scholar 

  11. Zhang S, Royer R, Li S, McLaughlin JR, Rosen B, Risch HA, et al. Frequencies of BRCA1 and BRCA2 mutations among 1,342 unselected patients with invasive ovarian cancer. Gynecol Oncol. 2011;121:353–7.

    Article  CAS  Google Scholar 

  12. Narod SA, Moody JR, Rosen B, Fan I, Risch A, Sun P, et al. Estimating survival rates after ovarian cancer among women tested for BRCA1 and BRCA2 mutations. Clin Genet. 2013;83:232–7.

    Article  CAS  Google Scholar 

  13. Kurman RJ, Carcangiu ML, Herrington CS, Young RH. WHO Classification of tumours of female reproductive organs. 4th edn. Lyon: IARC; 2014.

  14. Kim SJ, Rosen B, Fan I, Ivanova A, McLaughlin JR, Risch H, et al. Epidemiologic factors that predict long-term survival following a diagnosis of epithelial ovarian cancer. Br J Cancer. 2017;116:964–71.

    Article  Google Scholar 

  15. Pal T, Akbari MR, Sun P, Lee JH, Fulp J, Thompson Z, et al. Frequency of mutations in mismatch repair genes in a population-based study of women with ovarian cancer. Br J Cancer. 2012;107:1783–90.

    Article  CAS  Google Scholar 

  16. Kotsopoulos J, Sopik V, Rosen B, Fan I, McLaughlin JR, Risch H, et al. Frequency of germline PALB2 mutations among women with epithelial ovarian cancer. Fam Cancer. 2017;16:29–34.

    Article  CAS  Google Scholar 

  17. Breast Cancer Association Consortium, Dorling L, Carvalho S, Allen J, González-Neira A, Luccarini C, et al. Breast cancer risk genes-association analysis in more than 113,000 women. N. Engl J Med. 2021;384:428–39.

    Article  Google Scholar 

  18. Kotsopoulos J, Rosen B, Fan I, Moody J, McLaughlin JR, Risch H, et al. Ten-year survival after epithelial ovarian cancer is not associated with BRCA mutation status. Gynecol Oncol. 2016;140:42–47.

    Article  CAS  Google Scholar 

  19. Lax SF. Pathology of endometrial carcinoma. Adv Exp Med Biol. 2017;943:75–96.

    Article  CAS  Google Scholar 

  20. Candido-dos-Reis FJ, Song H, Goode EL, Cunningham JM, Fridley BL, Larson MC, et al. Germline mutation in BRCA1 or BRCA2 and ten-year survival for women diagnosed with epithelial ovarian cancer. Clin Cancer Res. 2015;21:652–7.

    Article  CAS  Google Scholar 

  21. Lavie O, Chetrit A, Novikov I, Sadetzki S, National Israeli Study of Ovarian Cancer. Fifteen-year survival of invasive epithelial ovarian cancer in women with BRCA1/2 mutations—the National Israeli Study of Ovarian Cancer. Gynecol Oncol. 2019;153:320–5.

    Article  Google Scholar 

  22. Møller P, Seppälä T, Bernstein I, Holinski-Feder E, Sala P, Evans DG, et al. Incidence of and survival after subsequent cancers in carriers of pathogenic MMR variants with previous cancer: a report from the prospective Lynch syndrome database. Gut. 2017;66:1657–64.

    Article  Google Scholar 

  23. Stewart CJ, Bowtell DD, Doherty DA, Leung YC. Long-term survival of patients with mismatch repair protein-deficient, high-stage ovarian clear cell carcinoma. Histopathology. 2017;70:309–13.

    Article  Google Scholar 

  24. Wokołorczyk D, Kluźniak W, Stempa K, Rusak B, Huzarski T, Gronwald J, et al. PALB2 mutations and prostate cancer risk and survival. Br J Cancer. 2021;125:569–75.

    Article  Google Scholar 

  25. Cybulski C, Kluźniak W, Huzarski T, Wokołorczyk D, Kashyap A, Jakubowska A, et al. Clinical outcomes in women with breast cancer and a PALB2 mutation: a prospective cohort analysis. Lancet Oncol. 2015;16:638–44.

    Article  CAS  Google Scholar 

  26. Poole EM, Konstantinopoulos PA, Terry KL. Prognostic implications of reproductive and lifestyle factors in ovarian cancer. Gynecol Oncol. 2016;142:574–87.

    Article  Google Scholar 

  27. Poole EM, Merritt MA, Jordan SJ, Yang HP, Hankinson SE, Park Y, et al. Hormonal and reproductive risk factors for epithelial ovarian cancer by tumor aggressiveness. Cancer Epidemiol Biomark Prev. 2013;22:429–37.

    Article  CAS  Google Scholar 

  28. Fortner RT, Poole EM, Wentzensen NA, Trabert B, White E, Arslan AA, et al. Ovarian cancer risk factors by tumor aggressiveness: an analysis from the Ovarian Cancer Cohort Consortium. Int J Cancer. 2019;145:58–69.

    Article  CAS  Google Scholar 

  29. Daly MB, Pal T, Berry MP, Buys SS, Dickson P, Domchek SM, et al. Genetic/familial high-risk assessment: breast, ovarian, and pancreatic, version 2.2021, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2021;19:77–102.

    Article  CAS  Google Scholar 

  30. Pennington KP, Walsh T, Harrell MI, Lee MK, Pennil CC, Rendi MH, et al. Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas. Clin Cancer Res. 2014;20:764–75.

    Article  CAS  Google Scholar 

  31. Rosen B, Laframboise S, Ferguson S, Dodge J, Bernardini M, Murphy J, et al. The impacts of neoadjuvant chemotherapy and of debulking surgery on survival from advanced ovarian cancer. Gynecol Oncol. 2014;134:462–7.

    Article  CAS  Google Scholar 

  32. Kwa M, Edwards S, Downey A, Reich E, Wallach R, Curtin J, et al. Ovarian cancer in BRCA mutation carriers: improved outcome after intraperitoneal (IP) cisplatin. Ann Surg Oncol. 2014;21:1468–73.

    Article  Google Scholar 

Download references


We acknowledge Isabel Fan for coordinating this study and the study participants for their involvement in this research study.


This study was supported by US National Institutes of Health grants R01-CA063678 (Narod); R01-CA063682 (Risch); and the Peter Gilgan Center for Women’s Cancers at Women’s College Hospital, in partnership with the Canadian Cancer Society. Joanne Kotsopoulos is a recipient of a Tier II Canada Research Chair. SAN is the recipient of a Tier I Canada Research Chair.

Author information

Authors and Affiliations



SAN had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: JK and SAN. Acquisition, analysis or interpretation of the data: all authors. Drafting of the manuscript: JK and SAN. Critical revision of the manuscript for important intellectual content: all authors. Statistical analysis: JK, SAN, PS and MRA. Obtained funding: SAN. Administrative, technical or material support: PS, NZ and MRA. Study supervision: JK and SAN.

Corresponding author

Correspondence to Steven A. Narod.

Ethics declarations

Competing interests

SAN is an editorial board member of BJC. The remaining authors declare no competing interests.

Ethics approval and consent to participate

All of the women provided written informed consent and the study was approved by the institutional review boards of the University of Toronto and Yale University. The study was performed in accordance with the Declaration of Helsinki.

Consent to publish

Individual personal data not included.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kotsopoulos, J., Zamani, N., Rosen, B. et al. Impact of germline mutations in cancer-predisposing genes on long-term survival in patients with epithelial ovarian cancer. Br J Cancer 127, 879–885 (2022).

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:


Quick links